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Introduction. Favipiravir is one of the most well-known broad-spectrum drugs against many RNA viruses, including the severe acute respiratory syndrome virus 2 [severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)]. Due to its structure, favipiravir is embedded in the RNA of the virus and blocks its further replication in the cell of the human body. Favipiravir is also included in the list of vital and essential medicines, which confirms the importance for Russian healthcare of this drug in the fight against common RNA viruses. We have already published bioanalytical methods for determining favipiravir in human blood plasma by high-performance liquid chromatography with an ultraviolet detector (HPLC–UV) in order to study the pharmacokinetics of favipiravir with parenteral administration (the analytical range of the technique was 0.25–200.00 µg/ ml for the dosage of favipiravir 400 mg in 1 vial of lyophilizate for the preparation of concentrate for the preparation of solution for infusions) and by HPLC with tandem mass-selective detection (HPLC-MS/MS) in order to study the pharmacokinetics of β-D-N4-hydroxycytidine and favipiravir in their joint determination in blood plasma with oral administration (the analytical range of the technique was 250.00–20000.00 ng/ml for the dosage of favipiravir 400 mg in 1 tablet). The expectation of low favipiravir’s concentrations (the dosage of favipiravir in the drugs in question is 200 mg in 1 tablet in this study) and, in this regard, the expansion of the range by reducing the value of the lower limit of quantitative determination (LLOQ) used in this study necessitates the development of another method. Therefore, this study is given the development and validation of a method for determining favipiravir in human blood plasma by HPLC-MS/MS with an analytical range of 50.00–15000.00 ng/ml.Aim. The aim of this study is to develop a method for quantitative determination of favipiravir in human blood plasma by HPLC-MS/MS for further for further researches of pharmacokinetics and bioequivalence of drugs.Materials and methods. In the process of sample preparation, a method of proteins precipitation with methanol was used. A solution labeled with stable isotopes of favipiravir-13C3 was used as an internal standard, the mobile phase was a 0.1 % solution of formic acid in water (eluent A) and methanol (eluent B). Chromatographic column – Phenomenex Kinetex C18, 100×3.0 mm. The determination of favipiravir in human blood plasma was carried out by HPLC using a tandem mass spectrometric detector with a triple quadrupole. The analytical range for favipiravir is 50.00– 15000.00 ng/ml in human blood plasma.Results and discussion. This method was validated by selectivity, calibration curve, accuracy, precision, matrix effect, spike recovery, carry-over effect, the lower limit of quantification and stability.Conclusion. A method of quantitative favipiravir’s determination in human blood plasma by HPLC-MS/MS with a confirmed analytical range of 50.00–15000.00 ng/ml in human blood plasma has been developed and validated. This method allows using it for the analytical part of pharmacokinetics and bioequivalence studies of drugs containing favipiravir in order to expand their range in the domestic pharmaceutical market.
Introduction. Favipiravir is one of the most well-known broad-spectrum drugs against many RNA viruses, including the severe acute respiratory syndrome virus 2 [severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)]. Due to its structure, favipiravir is embedded in the RNA of the virus and blocks its further replication in the cell of the human body. Favipiravir is also included in the list of vital and essential medicines, which confirms the importance for Russian healthcare of this drug in the fight against common RNA viruses. We have already published bioanalytical methods for determining favipiravir in human blood plasma by high-performance liquid chromatography with an ultraviolet detector (HPLC–UV) in order to study the pharmacokinetics of favipiravir with parenteral administration (the analytical range of the technique was 0.25–200.00 µg/ ml for the dosage of favipiravir 400 mg in 1 vial of lyophilizate for the preparation of concentrate for the preparation of solution for infusions) and by HPLC with tandem mass-selective detection (HPLC-MS/MS) in order to study the pharmacokinetics of β-D-N4-hydroxycytidine and favipiravir in their joint determination in blood plasma with oral administration (the analytical range of the technique was 250.00–20000.00 ng/ml for the dosage of favipiravir 400 mg in 1 tablet). The expectation of low favipiravir’s concentrations (the dosage of favipiravir in the drugs in question is 200 mg in 1 tablet in this study) and, in this regard, the expansion of the range by reducing the value of the lower limit of quantitative determination (LLOQ) used in this study necessitates the development of another method. Therefore, this study is given the development and validation of a method for determining favipiravir in human blood plasma by HPLC-MS/MS with an analytical range of 50.00–15000.00 ng/ml.Aim. The aim of this study is to develop a method for quantitative determination of favipiravir in human blood plasma by HPLC-MS/MS for further for further researches of pharmacokinetics and bioequivalence of drugs.Materials and methods. In the process of sample preparation, a method of proteins precipitation with methanol was used. A solution labeled with stable isotopes of favipiravir-13C3 was used as an internal standard, the mobile phase was a 0.1 % solution of formic acid in water (eluent A) and methanol (eluent B). Chromatographic column – Phenomenex Kinetex C18, 100×3.0 mm. The determination of favipiravir in human blood plasma was carried out by HPLC using a tandem mass spectrometric detector with a triple quadrupole. The analytical range for favipiravir is 50.00– 15000.00 ng/ml in human blood plasma.Results and discussion. This method was validated by selectivity, calibration curve, accuracy, precision, matrix effect, spike recovery, carry-over effect, the lower limit of quantification and stability.Conclusion. A method of quantitative favipiravir’s determination in human blood plasma by HPLC-MS/MS with a confirmed analytical range of 50.00–15000.00 ng/ml in human blood plasma has been developed and validated. This method allows using it for the analytical part of pharmacokinetics and bioequivalence studies of drugs containing favipiravir in order to expand their range in the domestic pharmaceutical market.
Introduction. Favipiravir is an antiviral compound that inhibits the RNA-dependent polymerase and possesses antiviral properties against RNA viruses, including SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2). The new drug Areplivir® Zinc as a combination of favipiravir (200 mg) and zinc gluconate (70 mg) in the form of film-coated tablets has been developed by LLC "PROMOMED RUS", Russia. This combination of favipiravir and zinc gluconate could provide more effective treatment of COVID-19.Aim. The aim of the pharmacokinetics study is comparison between Areplivir® Zinc (INN: favipiravir + zinc gluconate), film-coated tablets (the manufacturer is JSC "Biokhimic", LLC "PROMOMED RUS" as registration certificate holder) and Areplivir® (INN: favipiravir), film-coated tablets (the manufacturer is JSC "Biokhimic", LLC "PROMOMED RUS" as registration certificate holder) to evaluate the effect of zinc on the favipiravir pharmacokinetics.Materials and methods. The clinical and analytical phases as well as pharmacokinetic analyses have been performed as a part of a phase I clinical trial. Chromatographic separation and detection of favipiravir were performed by high-performance liquid chromatography – tandem mass spectrometry (HPLC-MS/MS) method using Nexera XR high-performance liquid chromatograph with triple quadrupole tandem mass spectrometer LCMS-8040 (Shimadzu Corporation, Japan). The validated analytical range of the method was 50.00–15 000.00 ng/mL in human plasma. The plasma zinc concentrations were measured by a biochemical method with the use of the kit «Zinc-Novo (50)» (JSC "Vector-Best", Russia). The descriptive statistics were calculated using Microsoft Excel (Microsoft Corporation, USA). The pharmacokinetic parameters, analysis of variance (ANOVA), 90 % confidence intervals (90 % CIs) and the intra-subject variability (CVintra) were calculated by R Project 3.5.1 software (package «bear», version 2.8.3-2), originally created by Hsin-ya Lee and Yung-jin Lee, Taiwan.Results and discussion. The 90 % confidence intervals of the ratios for Сmax and AUC(0–t) were 86.48–100.38 % and 103.77–119.47 %, respectively. The 90 % confidence intervals were all within the acceptance range of 80.00–125.00 % which means there is no effect of zinc on the favipiravir pharmacokinetics. The intra-subject variability (CVintra) of favipiravir for the pharmacokinetic parameters Cmax and AUC(0–t) were 15.06 % and 14.23 %.Conclusion. The results justified the subsequent phases of clinical trials of Areplivir® Zinc (INN: favipiravir + zinc gluconate), film-coated tablets (LLC "PROMOMED RUS", Russia). This combination of favipiravir and zinc could expand the existing armamentarium of antiviral drugs for the treatment of COVID-19.
Although many efforts have been made to elucidate the pathogenesis of COVID-19, the underlying mechanisms are yet to be fully uncovered. However, it is known that a dysfunctional immune response and the accompanying uncontrollable inflammation lead to troublesome outcomes in COVID-19 patients. Pannexin1 channels are put forward as interesting drug targets for the treatment of COVID-19 due to their key role in inflammation and their link to other viral infections. In the present study, we selected a panel of drugs previously tested in clinical trials as potential candidates for the treatment of COVID-19 early on in the pandemic, including hydroxychloroquine, chloroquine, azithromycin, dexamethasone, ribavirin, remdesivir, favipiravir, lopinavir, and ritonavir. The effect of the drugs on pannexin1 channels was assessed at a functional level by means of measurement of extracellular ATP release. Immunoblot analysis and real-time quantitative reversetranscription polymerase chain reaction analysis were used to study the potential of the drugs to alter pannexin1 protein and mRNA expression levels, respectively. Favipiravir, hydroxychloroquine, lopinavir, and the combination of lopinavir with ritonavir were found to inhibit pannexin1 channel activity without affecting pannexin1 protein or mRNA levels. Thusthree new inhibitors of pannexin1 channels were identified that, though currently not being used anymore for the treatment of COVID-19 patients, could be potential drug candidates for other pannexin1-related diseases.
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